Inmunoterapia: para el paciente, no para el tumor

JM Piulats

TCR$ HLAI$

TCR$ HLAI$

PD#1%

TCR$ HLAI$

PD#1%

INFg

TCR$ HLAI$

PD#1%

INFg

PD#L1%

TCR$ HLAI$

PD1$ PDL1$

Adaptive Immune Resistance

Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic

Lesions Supports an Adaptive Resistance Mechanism of immune Escape

JM Taube et al. Sci Transl Med 4, 127ra37 (2012)

Primary Tumors Metastasis

PD-1 blockade induces responses by inhibiting adaptive

immune resistance

Spatiotemporal dynamics of CD8+

Realising PD-1 checkpoint lead to:

1. T-cell proliferation.

2. Intratumoral infiltration.

3. Increased effector function.

PC Tumeh et al. Nature 515, 568-571 (2014)

PD-1 blockade induces responses by inhibiting adaptive

immune resistance

TCR clonality:

PC Tumeh et al. Nature 515, 568-571 (2014)

TCR Clonality

ASCO clonalidad linfo B

Atezo y vejiga

Low Diversity

High Clonality

High Diversity

Low Clonality

SA Funt et al. ASCO Abs 3005 (2016)

Peripheral and Intratumoral T Cell Receptor Clonality Correlate

with Clinical Outcomes in Pts with Metastatic Urotelial Cancer

Treated with Atezolizumab

Intratumoral TCR Clonality

Spontaneus

Treatment

Induced

Spontaneus

Treatment

Induced

Spontaneus

Treatment

Induced

Spontaneus

Treatment

Induced

Spontaneus

Treatment

Induced

Spontaneus

Treatment

Induced

COMBINATION

Spontaneus

Treatment

Induced

COMBINATION

Spontaneus

Treatment

Induced

COMBINATION

MS Lawrence et al. Nature 499, 214-218 (2013)

Somatic mutation frequencies observed in exomes from 3,083

tumor–normal pairs.

Can we identify which tumors might benefit Monotherapy or Combination?

MS Lawrence et al. Nature 499, 214-218 (2013)

Somatic mutation frequencies observed in exomes from 3,083

tumor–normal pairs.

Can we identify which tumors might benefit Monotherapy or Combination?

A Snyder et al. NEJM 371, 2189-2199 (2014)

NA Rizvi et al. Science 348, 124-128 (2015)

JE Rosenberg et al. Lancet 387, 1909-19-20 (2016)

Defects in DNA-repairing genes as a source for DNA mutations, does it

predict response to check-point inhibitors?

NA Rizvi et al. Science 348, 124-128 (2015)

Defects in DNA-repairing genes as a source for DNA mutations, does it

predict response to check-point inhibitors?

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

DT Le et al. New Engl J Med 372, 2509-2520 (2015)

Defects in DNA-repairing genes as a source for DNA mutations, does it

predict response to check-point inhibitors?

W Hugo et al. Cell 165, 35-44 (2016)

BRCA2 mutations are enriched in melanomas responsive to anti-PD-1.

Adaptive

Immune

Resistance

Intrinsic

Induction Tolerance Immunological

Ignorance

CD8 PDL1

Can we identify which tumors might benefit Monotherapy or Combination?

CY Ock et al. Clin Cancer Res 22, 2261-2270 (2016)

PD-L1 CD8A

PD-L1 CD8A

PD-L1 CD8A

PD-L1 CD8A

15

10

5 0

0

5

10

Log2 (CD8A)

Log2

(P

D-L

1)

C Robert et al. NEJM 372, 320-330 (2015)

MELANOMA

MELANOMA

J Brahmer et al. NEJM 373, 123-135 (2015)

LUNG CANCER (squamous)

LUNG CANCER (squamous)

H Borghaei et al. NEJM 373, 1627-1639 (2015)

LUNG CANCER (non-squamous)

BLADDER CANCER

Unpublished data presented at SITC 2016 by Dr Bellmunt

BLADDER CANCER

Unpublished data presented at SITC 2016 by Dr Bellmunt

HEAD & NECK

RL Ferris et al. NEJM 375, 1856-1867 (2016)

HEAD & NECK

RL Ferris et al. NEJM 375, 1856-1867 (2016)

RENAL CLEAR CELL CARCINOMA

RJ Motzer et al. NEJM 373, 1803-1813 (2015)

Static Biomarker

Static Biomarker

Dynamic Biomarker

YES NO

PD1/PDL1 blocking agents should be only effective in patients with pre-existing immune favorable environment in the tumor that is suppressed by PD1/PDL1 signal. Can tumor biopsy discriminate patients that will obtain benefit or not?

YES NO

Responder Non Responder

PD1/PDL1 blocking agents should be only effective in patients with pre-existing immune favorable environment in the tumor that is suppressed by PD1/PDL1 signal. Can tumor biopsy discriminate patients that will obtain benefit or not?

PD1/PDL1 blocking agents should be only effective in patients with pre-existing immune favorable environment in the tumor that is suppressed by PD1/PDL1 signal. Can tumor biopsy discriminate patients that will obtain benefit or not?

Viral Defense Gene Signature

KB Chiappinelli et al. Cell 162, 974-986 (2015)

Unpublished data presented at ASCO 2016 by Dr Velcheti

Immune checkpoint pathways are

non-redundant.

Interrogation of the immune

evasion pathways can guide

treatment with immune checkpoint

inhibitors.

AMG228 (Amgen)

INCAGN1876 (Incyte)

MK4166 (Merck)

MEDI1873 (Astra Zeneca)

No name (BMS)

INCAGN1949 (Incyte)

MEDI0562 (Astra Zeneca)

MEDI6383 (Astra Zeneca)

RG7888 (Roche)

Urelumab (BMS)

Utomilumab (Pfizer)

Ipilimumab (BMS)

Tremelimumab (Astra Zeneca)

Nivolumab (BMS)

Pembrolizumab (Merck)

REGN2810 (Regeneron)

MEDI0680 (Astra Zeneca)

PDR001 (Novartis)

INCSHR1210 (Incyte)

Atezolizumab (Roche)

Durvalumab (Astra Zeneca)

Avelumab (Pfizer)

BMS936559 (BMS)

PD-L1

MGB453 (Novartis)

BMS986016 (BMS)

LAG525 (Novartis)

No name (Merck)

CM24 (Merck) CEACAM1

CM24 (Daiichi Sanyo) B7-H3

Other Blocking Abs

Epacadostat (Incyte)

RG6078 (Roche)

No name (Merck)

BMS936559 (BMS)

IDO1

AMG319 (Amgen)

INCB50465 (Incyte)

Duvelisib (Abbvie)

PI3Kd and d/g

AMG319 (Amgen)

IRG7155 (Roche)

No name (BMS)

PLX73086 (Daiichi Sanyo)

PLX3397 (Daiichi Sanyo)

No name (Lilly)

CSF1R

Galunisertib

(Lilly)

TGFb

MK1966 (Merck)

IL10

AMG820 (Amgen)

c-fms

AMG221 – CEA/CD3 (Amgen)

AMG330 – CD33/CD3 (Amgen)

Blinatumomab – CD19/CD3 (Amgen)

MEDI565 – CEA/CD3 (Astra Zeneca)

REGN1979 – CD20/CD3 (Regeneron)

RG7802 – CEA/CD3 (Roche)

RG7813 – CEA/IL2 (Roche)

RG7828 – CD20/CD3 (Roche)

BiTEs

Lirilumab – KIRs (BMS)

Monalizumab – NKG2A (Innate)

IPH4102 – KIR3DL2 (Innate)

IPH4301 – MICA/B (Innate)

NKs

SD101 – TLR9 (Merck)

MEDI9197 – TLR7/8 (Astra Zeneca)

IPH33 – TLR3 (Innate)

TLR Agonists Others: JAK1/2; Vaccines; CXCR2; BTK; VEGF…

MONOTHERAPY Who might get benefit from single agent PD1/PDL1?

aPD1

COMBINATIONS

J Larkin et al. N Engl J Med 373, 23-34 (2015)

08/08/2014 22/10/2015 25/02/2015 09/09/2015